NAD(P)H:Quinone Oxidoreductase 1: Role as a Superoxide Scavenger

Siegel, David; Gustafson, Daniel L.; Dehn, Donna L.; Han, Jin; Boonchoong, Preecha; Berliner, Lawrence J.; Ross, David

doi:10.1124/mol.65.5.1238

Cited by 407 publications

(282 citation statements)

References 46 publications

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“…NQO1 is a phase 2 enzyme that participates in the detoxification of dopamine-derived quinone molecules and ROS (Siegel et al, 1997;Ross, 2004;Siegel et al, 2004;Zafar et al, 2006). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

et al. 2008

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Evidence suggests oxidative and electrophilic stress as a major factor contributing to the neuronal cell death in neurodegenerative disorders, especially Parkinson's disease. Consistent with this concept, administration of exogenous antioxidants has been shown to be protective against oxidative/ electrophilic neurodegeneration. However, whether induction of endogenous antioxidants and phase 2 enzymes by the unique chemoprotectant, 3H-1,2-dithiole-3-thione (D3T) in neuronal cells also affords protection against oxidative and electrophilic neurocytotoxicity has not been carefully investigated. In this study, we showed that incubation of SH-SY5Y neuroblastoma cells or primary human neurons with micromolar concentrations (10-100 μM) of D3T for 24 h resulted in significant increases in the levels of reduced glutathione (GSH) and NAD(P)H:quinone oxidoreductase 1 (NQO1), two crucial cellular defenses against oxidative and electrophilic stress. D3T treatment also caused increases in mRNA expression of γ-glutamylcysteine ligase catalytic subunit and NQO1 in SH-SY5Y cells. In addition, D3T treatment of the neuronal cells also resulted in a marked elevation of GSH content in the mitochondrial compartment. To determine the protective effects of the D3T-induced cellular defenses on neurotoxicant-elicited cell injury, SH-SY5Y cells were pretreated with D3T for 24 h and then exposed to dopamine, 6-hydroxydopamine (6-OHDA), 4-hydroxy-2-nonenal (HNE), or H 2 O 2 , agents that are known to be involved in neuron degeneration. We observed that D3T-pretreatment of SH-SY5Y cells led to significant protection against the cytotoxicity elicited by the above neurotoxicants. Similar neurocytoprotective effects of D3T-pretreatment were also observed in primary human neurons exposed to 6-OHDA or HNE. Taken together, this study demonstrates that D3T potently induces neuronal cellular GSH and NQO1 as well as mitochondrial GSH, and that such upregulated endogenous defenses are accompanied by increased resistance to oxidative and electrophilic neurocytotoxicity.

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Section: Resultsmentioning

confidence: 99%

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

et al. 2008

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Section: Introductionmentioning

confidence: 99%

“…NQO1 detoxifies quinines and their derivatives and prevents their participation in redox cycling, therefore reducing oxidative stress [3]. NQO1 also protects cells from oxidative stress by maintaining antioxidant forms of ubiquinone and vitamin E. Furthermore, recent reports show that highly expressed and inducible endogenous NQO1 in cardiovascular cells may act as a potential superoxide scavenger [4,5].Atherosclerotic lesions preferentially develop in areas of the vasculature that are exposed to non-laminar blood flow, whereas laminar flow is atheroprotective [6].Exposure of endothelial cells to laminar flow activates antioxidant response element (ARE)-driven transcriptional activity and increases the expression of a set of ARE-regulated genes, including NQO1, HO-1 (heme oxygenase-1) and GST (glutathione S-transferase) [7]. These findings suggest that NQO1 is an important enzyme in protecting vessels against oxidative stress and atherogenesis.…”

mentioning

confidence: 99%

The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes

Han

Kang

Kim

et al. 2009

Molecular Genetics and Metabolism

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“…Elevated levels of O 2 − have been observed in PDH deficient fibroblasts, probably produced at the Q 0 site in complex III. 16 We were unable to detect ROS production in fibroblasts of patients, however the overexpression of antioxidant enzymes MnSOD and NQO1, which is also a superoxide scavenger, 17 demonstrates that electron leaking is indeed happening. Furthermore, NQO1 catalyzes NAD(P)H oxidation by reducing CoQ 10 18 that would compensate the redox balance of the high CoQ 10 content.…”

Section: Discussionmentioning

confidence: 87%

Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

et al. 2015

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Coenzyme Q 10 (CoQ 10 ) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ 10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ 10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ 10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ 10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders.

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NAD(P)H:Quinone Oxidoreductase 1: Role as a Superoxide Scavenger

Cited by 407 publications

References 46 publications

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes

Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content

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